Method for preparing intermediate of 4-methoxypyrrole derivative

Abstract

The present invention relates to a method for preparing intermediates of 4-methoxypyrrole derivatives. The preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.

Claims

1. A method for preparing a compound represented by the following Chemical Formula 1, comprising the steps of: 1) reacting a compound represented by the following Chemical Formula 1-1 with ammonium chloride and either sodium cyanide or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-2; 2) protecting a compound represented by the following Chemical Formula 1-2 with an amine protecting group (P) to prepare a compound represented by the following Chemical Formula 1-3; 3) reacting a compound represented by the following Chemical Formula 1-3 with (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-4; 4) reacting a compound represented by the following Chemical Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the following Chemical Formula 1-5; 5) reacting a compound represented by the following Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the following Chemical Formula 1-6; and 6) reacting a compound represented by the following Chemical Formula 1-6 with an acid to prepare a compound represented by the following Chemical Formula 1: ##STR00006## ##STR00007##

2. The method according to claim 1, wherein in the step 1, a molar ratio of the compound represented by the Chemical Formula 1-1 to ammonium chloride is 10:1 to 1:10 and a molar ratio of the compound represented by the Chemical Formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10.

3. The method according to claim 1, wherein in the step 1, the reaction with the compound represented by the Chemical Formula 1-1, ammonium chloride and either sodium cyanide or potassium cyanide is carried out at 0° C. to 40° C., and the reaction with an acid is carried out at 80° C. to 120° C.

4. The method according to claim 1, wherein the acid in the step 1 is either acetic acid or hydrochloric acid.

5. The method according to claim 1, wherein the amine protecting group (P) in the step 2 is either tert-butoxycarbonyl, fluorenylmethyloxycarbonyl, Tosyl, or Acyl.

6. The method according to claim 1, wherein the reaction of the step 2 is carried out at 10° C. to 40° C.

7. The method according to claim 1, wherein the magnesium halide in the step 3 is either magnesium chloride or magnesium bromide.

8. The method according to claim 1, wherein in the step 3, a molar ratio of the compound represented by the Chemical Formula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1 to 1:10, a molar ratio of the compound represented by the Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, and a molar ratio of the compound represented by the Chemical Formula 1-3 to the magnesium halide is 10:1 to 1:10.

9. The method according to claim 1, wherein the acid in the step 3 is either hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.

10. The method according to claim 1, wherein the reaction between the compound represented by the Chemical Formula 1-3 and (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide in the step 3 is carried out at 50° C. to 100° C., and the reaction with the acid is carried out at 0° C. to 40° C.

11. The method according to claim 1, wherein a molar ratio of the compound represented by the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal in the step 4 is 1:1 to 1:10.

12. The method according to claim 1, wherein the reaction of the step 4 is carried out at 20° C. to 70° C.

13. The method according to claim 1, wherein a molar ratio of the compound represented by the Chemical Formula 1-5 to dimethylsulfate in the step 5 is 10:1 to 1:10.

14. The method according to claim 1, wherein the reaction of the step 5 is carried out at 20° C. to 60° C.

15. The method according to claim 1, wherein the acid in the step 6 is trifluoroacetic acid and a molar ratio of the compound represented by the Chemical Formula 1-6 to the trifluoroacetic acid in the step 6 is 1:1 to 1:30.

16. The method according to claim 1, wherein the reaction of the step 6 is carried out at 10° C. to 40° C.

17. The method according to claim 1, wherein the acid of the step 6 is either trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

(1) Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention thereto. On the other hand, in the example and comparative example, the compounds prepared in each step are used in the next steps, and each step can produce more products than those described below for the next step.

Example

(2) ##STR00004##

(3) (Step 1)

(4) 35.8 g of ammonium chloride and 26.9 g of sodium cyanide were added to a flask, and 716.0 mL of ammonium hydroxide (25 to 28%) was added and then stirred for 10 minutes. The mixture was cooled to 0 to 5° C., stirred for 10 minutes, then heated to room temperature, and stirred for 15 minutes. After cooling to 0 to 5° C., 100.0 g of the prepared 2,4-difluorobenzaldehyde (Chemical Formula 1-1) and 770.0 mL of methanol-containing solution was slowly added to another flask for 15 to 20 minutes. The temperature was raised to room temperature, and the mixture was stirred for 22 hours to complete the first reaction. After concentration under reduced pressure at 50° C., 983.0 mL of acetic acid and 983.0 mL of conc.HCl were added, and refluxed at 100 to 105° C. (internal temperature) for 5 hours to complete the second reaction. It was concentrated under reduced pressure at 75° C., and the solvent was removed until a solid was precipitated. After purified water was added, the crystals were precipitated by stirring. The pH was adjusted to 6.5 using 5M-NaOH solution at internal temperature of 25° C. or less. Ethanol was added thereto and stirred at 10 to 15° C. for 1 hour. After filtration under reduced pressure, the filtrate was washed with ethanol. The resulting solid was dried under reduced pressure to obtain 78.4 g of the compound represented by the Chemical Formula 1-2 (yield: 59.5%).

(5) (Step 2)

(6) 100.0 g of the compound represented by the Chemical Formula 1-2 prepared in step 1, 1.5 L of THF and 1.5 L of purified water were added to a flask, and then stirred at room temperature for 10 minutes. The internal temperature was cooled to 0 to 5° C., and 134.6 g of sodium hydrogencarbonate and 139.5 g of di-tert-butyl dicarbonate were added thereto. The mixture was stirred at an internal temperature of 20 to 30° C. for 12 hours to complete the reaction, followed by concentration under reduced pressure at 45° C. After ethyl acetate was added, the internal temperature was cooled to 10° C. or lower. The pH was adjusted to 2.5 using 6N—HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45° C. to obtain 151.2 g of the compound represented by the Chemical Formula 1-3 (yield: 98.5%).

(7) .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.13-8.14 (d, 1H), 7.37-7.42 (m, 1H), 6.82-6.89 (m, 2H), 5.46-5.47 (d, 1H), 1.23 (s, 9H)

(8) (Step 3)

(9) 100.0 g of the compound represented by the Chemical Formula 1-3 prepared in step 2, 61.9 g of carbonyldiimidazole and 1.0 L of acetonitrile were added to a flask, and then stirred at room temperature for 1 hour. 59.8 g of methyl potassium malonate, 36.4 g of anhydrous magnesium chloride, 1.0 L of acetonitrile and 38.8 g of triethylamine were added to another flask and then stirred at 20 to 30° C. for 1 hour. The reactants of the two flasks were mixed and refluxed at an external temperature of 80° C. for 1 hour to complete the reaction. After cooling to room temperature, purified water was added. After cooling the internal temperature to 5 to 10° C., stirring was carried out for 1 hour. The obtained solid was filtered under reduced pressure and washed with purified water. Since the obtained crystal is a magnesium salt, the following salt dissociation process was carried out.

(10) The magnesium salt prepared above, 1.5 L of ethyl acetate and 1.0 L of purified water were added to a flask and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N—HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45° C. to prepare 97.3 g of the compound represented by the Chemical Formula 1-4 (yield: 81.4%).

(11) .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.26-7.30 (m, 1H), 6.85-6.92 (m, 2H), 5.83 (s, 1H), 5.64-5.65 (d, 1H), 3.67 (s, 3H), 3.38-3.52 (dd, 2H), 1.41 (s, 9H)

(12) (Step 4)

(13) 100.0 g of the compound represented by the Chemical Formula 1-4 prepared in step 3, and 2.0 L of toluene were added to a flask, and then stirred at room temperature for 10 minutes. 104.1 g of N,N-dimethylformamide dimethylacetal was added and stirred at 40° C. for 4 hours to complete the reaction. After concentration under reduced pressure at 45° C., ethyl acetate and purified water were added to the concentrated residue, and then stirred for 10 minutes. The pH was adjusted to 7.0 using 1N—HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45° C. to produce 79.2 g of the compound represented by the Chemical Formula 1-5 (yield: 77.0%). On the other hand, the compound represented by the Chemical Formula 1-5 was unstable (aerial oxidation occurred), the following step 5 was continuously carried out by an in-situ process.

(14) .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.73 (s, 1H), 7.48 (s, 1H), 7.38-7.43 (q, 1H), 6.83-6.95 (tt, 2H), 3.90 (s, 3H), 1.39 (s, 9H)

(15) (Step 5)

(16) 100.0 g of the compound represented by the Chemical Formula 1-5 prepared in step 4, and 1.5 L of acetone were added to a flask, and then stirred at room temperature for 10 minutes. 78.2 g of potassium carbonate, and 42.9 g of dimethyl sulfate were added thereto, and then stirred at 40° C. for 6 hours to complete the reaction. After cooling to room temperature, purified water and ethyl acetate were added and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N—HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45° C. to obtain 90.6 g of the compound represented by the Chemical Formula 1-6 (yield: 87.1%). Then, the following step 6 was carried out by an in-situ process without further purification.

(17) .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.87 (s, 1H), 7.31-7.36 (q, 1H), 6.84-6.95 (tt, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 1.38 (s, 9H)

(18) (Step 6)

(19) 100.0 g of the compound represented by the Chemical Formula 1-6 prepared in step 5, and 500.0 mL of methylene chloride were added to a flask, and then stirred at room temperature for 10 minutes. 310.4 g of trifluoroacetic acid was added and stirred at room temperature for 6 hours to complete the reaction. After cooling to 0 to 5° C., purified water was slowly added at 15° C. or lower. The pH was adjusted to 7.0 using a 50.0% NaOH solution at 15° C. or lower. Ethyl acetate was added and stirred for 10 minutes. The organic layer was extracted and dried over anhydrous magnesium sulfate. The celite washed with ethyl acetate was placed on a filter, and the organic layer was filtered under reduced pressure and then concentrated under reduced pressure at 45° C. Ethyl acetate was added to the concentrated residue and suspended by stirring. n-Hexane was added thereto, the internal temperature was cooled to 0 to 5° C., and the mixture was stirred for 1 hour. The obtained solid was filtered under reduced pressure. The filtrate was washed with n-hexane, and then dried under reduced pressure to obtain 65.5 g of the compound represented by the Chemical Formula 1 (yield: 90.0%).

(20) .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.78 (s, 1H), 8.12 (m, 1H), 7.30 (d, 1H), 6.95 (t, 1H), 6.88 (t, 1H), 3.87 (s, 3H), 3.85 (s, 3H)

Comparative Example

(21) ##STR00005##

(22) The preparation method was carried out as follows in the same manner as in steps 8-1 to 8-3 of Example 8 of Korean Patent No. 10-1613245.

(23) (Step 1)

(24) 2,4-Difluorophenylglycine (Chemical Formula 2-1, 150.0 g, 801.5 mmol), dimethyl 2-(methoxymethylene)malonate (Chemical Formula 2-2, 126.9 g, 728.6 mmol), and sodium acetate (65.8 g, 801.5 mmol) were added to methanol (800.0 ml), and then refluxed at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove about 70% of methanol, and then filtered. The resulting solid was dried under reduced pressure to produce 190.0 g of the compound represented by the Chemical Formula 2-3 (yield: 79.2%).

(25) .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.02-7.99 (m, 1H), 7.45-7.40 (m, 1H), 7.00-6.95 (m, 2H), 5.16 (s, 1H), 3.74 (s, 3H), 3.76 (s, 3H)

(26) (Step 2)

(27) Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added to the compound represented by the Chemical Formula 2-3 (190.0 g, 577.1 mmol) prepared in step 1. The reaction mixture was refluxed at 140° C. for 30 minutes and then cooled to 0° C. To the reaction mixture, ice water (577.1 ml) was added at 0° C., stirred at room temperature for 1 hour and then extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting compound was filtered using a silica gel to remove a solid, and then concentrated under reduced pressure to prepare the compound represented by the Chemical Formula 2-4, which was then used in the following step 3.

(28) (Step 3)

(29) Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added to the resulting residue, cooled to 0° C., followed by addition of sodium hydroxide (46.17 g, 1154.2 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, neutralized using 1N hydrochloric acid aqueous solution and then extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to produce 22.0 g of the compound represented by the Chemical Formula 2-5 (yield: 15.1%) (including steps 2 and 3).

(30) .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.80 (s, 1H), 8.17-8.12 (m, 2H), 7.13 (d, 1H), 6.95 (t, 1H), 6.86-6.83 (m, 1H), 3.88 (s, 3H)

(31) (Step 4)

(32) The compound represented by the Chemical Formula 2-5 (22.0 g, 86.9 mmol) prepared in step 3 was dissolved in tetrahydrofuran (434.5 ml) and methanol (173.9 ml). (Trimethylsilyl)diazomethane (2.0M diethyl ether solution, 173.8 ml) was added to the reaction mixture and then stirred at room temperature for 48 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to produce 18.1 g of the compound represented by the Chemical Formula 1 (yield: 75.3%).

(33) .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.78 (s, 1H), 8.12 (m, 1H), 7.30 (d, 1H), 6.95 (t, 1H), 6.88 (t, 1H), 3.87 (s, 3H), 3.85 (s, 3H)

Comparison of Examples and Comparative Examples

(34) The yields of the preparation methods of the Example and Comparative Example are shown in Table 1 below.

(35) TABLE-US-00001 TABLE 1 Example Comparative Example Total yield 28.8% 9.0% Total yield from 48.4% 9.0% 2,4-difluorophenylglycine to Chemical Formula 1

(36) As shown Table 1, it was confirmed that the Example according to the present invention could not only reduce the production cost by using inexpensive aldehyde as a starting material but also improve the yield by about 5.4 times as compared with the Comparative Example.

(37) In particular, both step 2 of Example according to the present invention and step 1 of Comparative Example used 2,4-difluorophenylglycine as a starting material. Comparing the methods for preparing the compound represented by the Chemical Formula 1 from the above step, Example according to the present invention showed a yield of about 50%, whereas Comparative Example showed a yield of 9%, thereby confirming that the yield according to the present invention was remarkably improved.

(38) In addition, in Example according to the present invention, the relatively low temperature was applied in the entire steps, whereas in step 2 of Comparative Example, the reaction temperature of about 140° C. was applied. Thus, the preparation method according to the present invention has an advantage that a relatively low reaction temperature can be applied. Furthermore, step 4 of Comparative Example used (trimethylsilyl)diazomethane which is an explosive reaction material, whereas Example according to the present invention has the advantage that such a reactant was not used.